1,4-diazabicycloalkane derivatives, their preparation and use

ABSTRACT

This invention relates to novel 1,4-diazabicycloalkane derivatives and their use in the manufacture of pharmaceutical compositions. The compounds of the invention are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. 
     Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

This application is the National Phase of PCT International applicationNo. PCT/DK2003/000639 filed on Sep. 29, 2003, which claims priorityunder 35 U.S.C. 119(e) to U.S. Provisional Application No(s). 60/426,368 filed on Nov. 15, 2002.

TECHNICAL FIELD

This invention relates to novel 1,4-diazabicycloalkane derivatives andtheir use in the manufacture of pharmaceutical compositions. Thecompounds of the invention are found to be cholinergic ligands at thenicotinic acetylcholine receptors and modulators of the monoaminereceptors and transporters.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),the peripheral nervous system (PNS), diseases or disorders related tosmooth muscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, pain, and withdrawal symptoms caused by the terminationof abuse of chemical substances.

BACKGROUND ART

The endogenous cholinergic neurotransmitter, acetylcholine, exert itsbiological effect via two types of cholinergic receptors, the muscarinicAcetyl Choline Receptors (mAChR) and the nicotinic Acetyl CholineReceptors (nAChR).

As it is well established that muscarinic acetylcholine receptorsdominate quantitatively over nicotinic acetylcholine receptors in thebrain area important to memory and cognition, and much research aimed atthe development of agents for the treatment of memory related disordershave focused on the synthesis of muscarinic acetylcholine receptormodulators.

Recently, however, an interest in the development of nAChR modulatorshas emerged. Several diseases are associated with degeneration of thecholinergic system i.e. senile dementia of the Alzheimer type, vasculardementia and cognitive impairment due to the organic brain damagedisease related directly to alcoholism. Indeed several CNS disorders canbe attributed to a cholinergic deficiency, a dopaminergic deficiency, anadrenergic deficiency or a serotonergic deficiency.

WO 00/34279 (Sanofi-Synthelabo) describes 1,4-diazabicyclo[3.2.2]nonanederivatives having activity at the nicotinic receptors. Onlysix-membered heteroaryl derivatives are described. The five-memberedheteroaryl derivatives of the present invention have not been described.

WO 01/55150 (Sanofi-Synthelabo) describes 1,4-diazabicyclo[3.2.2]nonanederivatives having activity at the nicotinic receptors. Only bicyclicheteroaryl derivatives are described. The monocyclic heteroarylderivatives of the present invention have not been described.

WO 01/92259 (Sanofi-Synthelabo) describes 1,4-diazabicyclo[3.2.2]nonanederivatives having activity at the nicotinic receptors. Onlyphenyl-isoxazole derivatives are described. The thiadiazole derivativesof the present invention have not been described.

WO 01/92260 (Sanofi-Synthelabo) describes 1,4-diazabicyclo[3.2.2]nonanederivatives having activity at the nicotinic receptors. Onlyphenyl-thiazole derivatives are described. The thiadiazole derivativesof the present invention have not been described.

EP 1219622 (Pfizer Ltd.) describes 1,4-diazabicyclo[3.2.2]nonanederivatives having activity at the nicotinic receptors. Only bicyclicheteroaryl derivatives are described. The monocyclic heteroarylderivatives of the present invention have not been described.

SUMMARY OF THE INVENTION

The present invention is devoted to the provision novel modulators ofthe nicotinic and/or of the monoamine receptors, which modulators areuseful for the treatment of diseases or disorders related to thecholinergic receptors, and in particular the nicotinic acetylcholinereceptor (nAChR), the monoamine receptors 5-HTR, DAR and NER, and thebiogenic amine transporters for 5-HT, DA and NE.

Due to their pharmacological profile the compounds of the invention maybe useful for the treatment of diseases or disorders as diverse as thoserelated to the cholinergic system of the central nervous system (CNS),the peripheral nervous system (PNS), diseases or disorders related tosmooth muscle contraction, endocrine diseases or disorders, diseases ordisorders related to neuro-degeneration, diseases or disorders relatedto inflammation, pain, and withdrawal symptoms caused by the terminationof abuse of chemical substances.

The compounds of the invention may also be useful as diagnostic tools ormonitoring agents in various diagnostic methods, and in particular forin vivo receptor imaging (neuroimaging), and they may be used inlabelled or unlabelled form.

In its first aspect the invention provides novel 1,4-diazabicycloalkanederivatives of Formula I

any of its enantiomers or any mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof, wherein

n is 1,2 or 3;

X represents O, S or Se; and

Ar represents a carbocyclic aromatic (aryl) group, or a heterocyclicaromatic (heteroaryl) group, which aromatic group may optionally besubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,alkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl,cycloalkoxy-alkoxy, halogen, CF₃, CN, NO₂, NH₂, carboxy, carbamoyl,amido, sulfamoyl, phenyl and benzyl.

In a second aspect the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of the1,4-diazabicycloalkane derivative of the invention, an enantiomer or amixture of enantiomers, or a pharmaceutically-acceptable addition saltthereof, together with at least one pharmaceutically-acceptable carrieror diluent.

Viewed from another aspect, the invention relates to the use of a1,4-diazabicycloalkane derivative of the invention, or an enantiomer ora mixture of enantiomers, or a pharmaceutically-acceptable addition saltthereof, for manufacture of a medicament for the treatment, preventionor alleviation of a disease or a disorder or a condition which isresponsive to modulation of cholinergic receptors and/or monoaminereceptors.

In yet another aspect the invention provides a method for treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease or disorder isresponsive to modulation of cholinergic receptors and/or monoaminereceptors, which method comprises the step of administering to such aliving animal body, including a human, in need thereof a therapeuticallyeffective amount of a 1,4-diazabicycloalkane derivative of theinvention, any of its enantiomers or any mixture of its enantiomers, ora pharmaceutically-acceptable addition salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

In its first aspect the present invention provides novel1,4-diazabicycloalkane derivatives represented by the general Formula I

any of its enantiomers or any mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof, wherein

n is 1, 2 or 3;

X represents O, S or Se; and

Ar represents a carbocyclic aromatic (aryl) group, or a heterocyclicaromatic (heteroaryl) group, which aromatic group may optionally besubstituted one or more times with substituents selected from the groupconsisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl,alkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl,cycloalkoxy-alkoxy, halogen, CF₃, CN, NO₂, NH₂, carboxy, carbamoyl,amido, sulfamoyl, phenyl and benzyl.

In a more preferred embodiment Ar represents a carbocyclic aromatic(aryl) group, or a heterocyclic aromatic (heteroaryl) group, whicharomatic group may optionally be substituted one or more times withsubstituents selected from the group consisting of alkyl, alkoxy,halogen, CF₃, CN, NO₂, NH₂ and phenyl.

In a first preferred embodiment the compound of the invention is a1,4-diazabicyclo[3.2.2]nonane derivative represented by Formula II

wherein

X and Ar are as defined above.

In a more preferred embodiment the compound of the invention is a4-thiadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative represented byFormula III

wherein Ar is as defined above.

In another preferred embodiment the compound of the invention is a4-oxadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative represented byFormula IV

wherein Ar is as defined above.

In a second preferred embodiment the carbocyclic aromatic (aryl) groupis an optionally substituted phenyl, indenyl, naphthyl, azulenyl,fluorenyl, or anthracenyl group.

In a more preferred embodiment the carbocyclic aromatic group is phenyl,optionally substituted one or two times with substituents selected fromthe group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,cycloalkoxy, halogen, CF₃, CN, NO₂, NH₂, carboxy, carbamoyl, amido,sulfamoyl, phenyl and benzyl.

In an even more preferred embodiment the carbocyclic aromatic group isphenyl, optionally substituted one or two times with substituentsselected from the group consisting of alkyl, alkoxy, halogen, CF₃, CN,NO₂, NH₂, and phenyl.

In a most preferred embodiment the4-thiadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of the inventionis

4-(5-Phenyl-1,3,4-thiadiazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;

or an enantiomer or a mixture of enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof;

and the 4-oxadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of theinvention is

-   4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Phenyl-phenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;    or-   4-[5-(2-Naphthyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;

or an enantiomer or a mixture of enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof.

In a third preferred embodiment the heterocyclic aromatic (heteroaryl)group is an optionally substituted aromatic monocyclic heterocyclicgroup, or an optionally substituted aromatic bi- or poly-heterocyclicheterocyclic group, which heterocyclic groups include benzo-fused 5- and6-membered heterocyclic rings containing one or more heteroatoms,selected from nitrogen (N), oxygen (O), sulphur (S) and/or selen (Se).

In a more preferred embodiment the aromatic monocyclic heterocyclicgroup is an optionally substituted aromatic 5- or 6-memberedheterocyclic monocyclic group.

In an even more preferred embodiment the optionally substituted aromaticmonocyclic heterocyclic group is furanyl, in particular 2-furanyl or3-furanyl; thienyl, in particular 2-thienyl or 3-thienyl; selenophenyl,in particular 2-selenophenyl or 3-selenophenyl; pyrrolyl (azolyl), inparticular 2-pyrrolyl or 3-pyrrolyl; oxazolyl, in particular oxazol-2-,4- or 5-yl; thiazolyl, in particular thiazol-2-, 4- or 5-yl; imidazolyl,in particular 2-imidazolyl or 4-imidazolyl; pyrazolyl, in particular3-pyrazolyl or 4-pyrazolyl; isoxazolyl, in particular isoxazol-3-, 4- or5-yl; isothiazolyl, in particular isothiazol-3-, 4- or 5-yl;oxadiazolyl, in particular 1,2,3-oxadiazol-4- or 5-yl, or1,3,4-oxadiazol-2-yl; triazolyl, in particular 1,2,3-triazol-4-yl or1,2,4-triazol-3-yl; thiadiazolyl, in particular 1,2,3-thiadiazol-4- or5-yl, or 1,3,4-thiadiazol-2-yl; pyridinyl, in particular 2-, 3- or4-pyridinyl; pyridazinyl, in particular 3- or 4-pyridazinyl;pyrimidinyl, in particular 2-, 4- or 5-pyrimidinyl; pyrazinyl, inparticular 2- or 3-pyrazinyl; and triazinyl, in particular 1,2,4- or1,3,5-triazinyl.

In another preferred embodiment the compound of the invention is a4-thiadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of Formula III,wherein Ar represents an optionally substituted aromatic monocyclicheterocyclic group selected from selenophenyl, in particular2-selenophenyl or 3-selenophenyl; imidazolyl, in particular2-imidazolyl, 4-imidazolyl or 5-imidazolyl; pyrazolyl, in particular3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl; thiazolyl, in particular2-thiazolyl or 5-thiazolyl; isothiazolyl, in particular 3-isothiazolyl,4-isothiazolyl or 5-isothiazolyl; oxadiazolyl, in particular1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl or 1,3,4-oxadiazol-2-yl;furazanyl, in particular 3-furazanyl; triazolyl, in particular1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl or1,2,4-triazol-5-yl; thiadiazolyl, in particular 1,3,4-thiadiazol-2-yl,1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; pyridazinyl, inparticular 3-pyridazinyl or 4-pyridazinyl; and triazinyl, in particular1,3,5-triazin-2-yl.

In a more preferred embodiment the aromatic 5- or 6-memberedheterocyclic monocyclic group is optionally substituted one or two timeswith substituents selected from the group consisting of alkyl, alkoxy,halogen, CF₃, CN, NO₂, NH₂ and phenyl.

In a most preferred embodiment the4-thiadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of the inventionis

-   4-[5-(2-Selenophenyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Selenophenyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-2-imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-4-imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-5-imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-3-pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-4-pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-5-pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Thiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Thiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Thiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Isothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Isothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Isothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Oxadizol-4-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Oxadizol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[1,3,4-Oxadizol-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Furazanyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Triazol-4-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,3-triazol-4-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,3-triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Triazol-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,4-triazol-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,4-triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,3,4-Thiadiazol-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Thiadiazol-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Thiadiazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Pyridazinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Pyridazinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;    or-   4-[5-(1,3,5-Triazin-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;

or an enantiomer or a mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof.

In yet another preferred embodiment the compound of the invention is a4-oxadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of Formula IV,wherein Ar represents an optionally substituted aromatic monocyclicheterocyclic group selected from furyl, in particular 2-furyl or3-furyl; pyridyl, in particular 2-pyridyl, 3-pyridyl or 4-pyridyl;thienyl, in particular 2-thienyl or 3-thienyl; pyrrolyl, in particular2-pyrrolyl or 3-pyrrolyl; pyrimidinyl, in particular 2-pyrimidinyl,4-pyrimidinyl or 5-pyrimidinyl; pyrazinyl; selenophenyl, in particular2-selenophenyl or 3-selenophenyl; oxazolyl, in particular 2-oxazolyl,4-oxazolyl or 5-oxazolyl; isoxazolyl, in particular 3-isoxazolyl,4-isoxazolyl or 5-isoxazolyl; imidazolyl, in particular 2-imidazolyl,4-imidazolyl or 5-imidazolyl; pyrazolyl, in particular 3-pyrazolyl,4-pyrazolyl or 5-pyrazolyl; thiazolyl, in particular 2-thiazolyl,4-thiazolyl or 5-thiazolyl; isothiazolyl, in particular 3-isothiazolyl,4-isothiazolyl or 5-isothiazolyl; oxadiazolyl, in particular1,2,3-oxadiazol4-yl, 1,2,3-oxadiazol-5-yl or 1,3,4-oxadiazol-2-yl;furazanyl, in particular 3-furazanyl; triazolyl, in particular1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl or1,2,4-triazol-5-yl; thiadiazolyl, in particular 1,3,4-thiadiazol-2-yl,1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; pyridazinyl, inparticular 3-pyridazinyl or 4-pyridazinyl; and triazinyl, in particular1,3,5-triazin-2-yl.

In a most preferred embodiment the4-oxadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of the inventionis

-   4-[5-(2-Furyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Furyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Thienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Thienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-2-pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-3-pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Pyrimidinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Pyrimidinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Pyrimidinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(Pyrazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Selenophenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Selenophenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Oxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Oxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Oxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Isoxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Isoxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Isoxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-2-imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-4-imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-5-imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-3-pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-4-pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-5-pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Thiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Thiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Thiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Isothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Isothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Isothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Oxadizol-4-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Oxadizol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,3,4-Oxadizol-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Furazanyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Triazol-4-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,3-Triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,3-triazol-4-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,3-triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Triazol-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,4-triazol-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-1,2,4-triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,3,4-Thiadiazol-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Thiadiazol-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,2,4-Thiadiazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Pyridazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(4-Pyridazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;    or-   4-[5-(1,3,5-Triazin-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;

or an enantiomer or a mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof.

In a fourth preferred embodiment the optionally substituted bicyclicaromatic heterocyclic group is indolyl, in particular 2-indolyl or3-indolyl; isoindolyl, in particular 1-isoindolyl or 3-isoindolyl;benzo[b]furanyl, in particular 2-benzo[b]furanyl or 3-benzo[b]furanyl;benzo[b]thienyl, in particular 2-benzo[b]thienyl or 3-benzo[b]thienyl;benzoimidazolyl, in particular 2-benzoimidazolyl; benzothiazolyl, inparticular 2-benzothiazolyl; quinolinyl, in particular 2-quinolinyl,3-quinolinyl or 4-quinolinyl; isoquinolinyl, in particular1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl; cinnolinyl, inparticular 3-cinnolinyl or 4-cinnolinyl; phthalazinyl, in particular1-phthalazinyl or 4-phthalazinyl; quinazolinyl, in particular2-quinazolinyl or 4-quinazolinyl; quinoxalinyl, in particular2-quinoxalinyl or 3-quinoxalinyl.

In a more preferred embodiment the optionally substituted polycyclicaromatic heterocyclic group is a tricyclic heteroaryl groups, inparticular 2-acridinyl, 3-acridinyl, 6-acridinyl or 7-acridinyl;carbazolyl, in particular 2-carbazolyl, 3-carbazolyl, 6-carbazolyl or7-carbazolyl; phenazinyl, in particular 2-phenazinyl, 3-phenazinyl,7-phenazinyl or 8-phenazinyl; phenothiazinyl, in particular2-phenothiazinyl, 3-phenothiazinyl, 7-phenothiazinyl or8-phenothiazinyl; and phenoxazinyl, in particular 2-phenoxazinyl,3-phenoxazinyl, 7-phenoxazinyl or 8-phenoxazinyl.

In an even more preferred embodiment the compound of the invention is a4-thiadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of Formula III,wherein the polycyclic aromatic heterocyclic group is an optionallysubstituted bicyclic heteroaryl selected from quinolinyl, in particular2-quinolinyl or 3-quinolinyl; isoquinolinyl, in particular3-isoquinolinyl; cinnolinyl, in particular 3-cinnolinyl; indolizinyl, inparticular 2-indolizinyl; benzimidazolyl, in particular2-benzimidazolyl; benzothiazolyl, in particular 2-benzothiazolyl;phthalazinyl, in particular 7-phthalazinyl; quinazolinyl, in particular2-quinazolinyl, quinoxalinyl, in particular 2-quinoxalinyl;naphthyridinyl, in particular 1,8-naphthyridin-2-yl or1,8-naphthyridin-3-yl; and acridinyl, in particular 2-acridinyl or3-acridinyl.

In a yet more preferred embodiment the bicyclic heteroaryl group isoptionally substituted one or two times with substituents selected fromthe group consisting of alkyl, alkoxy, halogen, CF₃, CN, NO₂, NH₂, andphenyl.

In a most preferred embodiment the4-thiadiazdlyl-1,4-diazabicyclo[3.2.2]nonane derivative of the inventionis

-   4-[5-(2-Quinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Quinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Isoquinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Cinnolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Indolizinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-2-indolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Benzimidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-2-benzimidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Benzothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(7-Phtalazinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Quinazolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Quinoxalinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,8-Naphthyridin-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,8-Naphthyridin-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Acridinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;    or-   4-[5-(3-Acridinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;

or an enantiomer or a mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof.

In yet another preferred embodiment the compound of the invention is a4-oxadiazolyl-1,4-diazabicyclo[3.2.2]nonane derivative of Formula IV,wherein Ar represents an optionally substituted aromatic monocyclicheterocyclic group selected from benzothienyl, in particular2-benzothienyl, 3-benzothienyl, 5-benzothienyl or 6-benzothienyl;benzofuryl, in particular 2-benzofuryl, 3-benzofuryl, 5-benzofuryl or6-benzofuryl; quinolinyl, in particular 2-quinolinyl or 3-quinolinyl;isoquinolinyl, in particular 3-isoquinolinyl; cinnolinyl, in particular3-cinnolinyl; indolizinyl, in particular 2-indolizinyl; indolyl, inparticular 2-indolyl; benzimidazolyl, in particular 2-benzimidazolyl;benzothiazolyl, in particular 2-benzothiazolyl; phthalazinyl, inparticular 7-phthalazinyl; quinazolinyl, in particular 2-quinazolinyl;quinoxalinyl, in particular 2-quinoxalinyl; naphthyridinyl, inparticular 1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl; acridinyl, inparticular 2-acridinyl or 3-acridinyl; dibenzofuryl, in particular2-dibenzofuryl, or 3-dibenzofuryl; dibenzothienyl, in particular2-dibenzothienyl or 3-dibenzothienyl; phenoxazinyl, in particular2-phenoxazinyl or 3-phenoxazinyl.

In a still more preferred embodiment the aromatic monocyclicheterocyclic group is optionally substituted one or two times withsubstituents selected from the group consisting of alkyl, alkoxy,halogen, CF₃, CN, NO₂, NH₂, and phenyl.

In a most preferred embodiment the compound of the invention is

-   4-[5-(2-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(6-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(5-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(6-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Quinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Quinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Isoquinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Cinnolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Indolizinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Indolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-2-indolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Benzimidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1-Methyl-2-benzimidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Benzothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(7-Phtalazinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Quinazolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Quinoxalinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,8-Naphthyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(1,8-Naphthyridin-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Acridinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Acridinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Dibenzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Dibenzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Dibenzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(3-Dibenzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;-   4-[5-(2-Phenoxazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;    or

4-[5-(3-Phenoxazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;

or an enantiomer or a mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof.

Any combination of two or more of the embodiments described herein isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contain of from one to eighteen carbon atoms (C₁₋₁₈-alkyl),more preferred of from one to six carbon atoms (C₁₋₆-alkyl; loweralkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyland isohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkylgroup, including butyl, isobutyl, secondary butyl, and tertiary butyl.In another preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

In the context of this invention a cycloalkyl-alkyl group designates acycloalkyl group as defined above, which cycloalkyl group is substitutedon an alkyl group as also defined above. Examples of preferredcycloalkyl-alkyl groups of the invention include cyclopropylmethyl andcyclopropylethyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to eight carbon atoms (C₂₋₈-alkenyl),more preferred of from two to six carbon atoms (C₂₋₆-alkenyl), includingat least one double bond. In a most preferred embodiment the alkenylgroup of the invention is ethenyl; 1- or 2-propenyl (allyl); 1-, 2- or3-butenyl, or 1,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexdienyl, or 1,3,5-hextrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or7-octenyl, or 1,3-octdienyl, or 1,3,5-octtrienyl, or1,3,5,7-octtetraenyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to eight carbon atoms (C₂₋₈-alkynyl),more preferred of from two to six carbon atoms (C₂₋₆-alkynyl), includingat least one triple bond. In its most preferred embodiment the alkynylgroup of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, or 1,3-butdiynyl; 1-, 2-, 3-, 4-pentynyl, or 1,3-pentdiynyl;1-, 2-, 3-, 4-, or 5-henynyl, or 1,3-hexdiynyl or 1,3,5-hextriynyl; 1-,2-, 3-, 4-, 5- or 6-heptynyl, or 1,3-heptdiynyl, or 1,3,5-hepttriynyl;1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, or 1,3-octdiynyl, or1,3,5octtriynyl, or 1,3,5,7-octtetraenyl.

In the context of this invention an alkoxy group designates an“alkyl-O—” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy groups of the invention include methoxy and ethoxy.

In the context of this invention an alkoxy-alkyl group designates an“alkyl-O-alkyl” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy-alkyl groups of the invention include methoxy-methyl,methoxy-ethyl, ethoxy-methyl, and ethoxy-ethyl.

In the context of this invention an alkoxy-alkoxy group designates an“alkyl-O-alkyl-O—” group, wherein alkyl is as defined above. Examples ofpreferred alkoxy-alkoxy groups of the invention include methoxy-methoxy,methoxy-ethoxy, ethoxy-methoxy, and ethoxy-ethoxy.

In the context of this invention a cycloalkoxy group designates a“cycloalkyl-O—” group, wherein cycloalkyl is as defined above.

In the context of this invention a cycloalkoxy-alkyl group designates a“cycloalkyl-O-alkyl” group, wherein cycloalkyl and alkyl are as definedabove.

In the context of this invention a cycloalkoxy-alkoxy group designates a“cycloalkyl-O-alkyl-O—” group, wherein cycloalkyl and alkyl are asdefined above.

In the context of this invention halogen represents a fluorine, achlorine, a bromine or an iodine atom. Thus, a trihalogenmethyl grouprepresents e.g. a trifluoromethyl group, a trichloromethyl group andsimilar trihalogen-substituted methyl groups.

In the context of this invention an acyl group designates a carboxygroup (—COOH) or an alkyl-carbonyl group (alkyl-CO—), wherein alkyl isas defined above. Examples of preferred acyl groups of the inventioninclude carboxy, acetyl, and propionyl.

Pharmaceutically Acceptable Salts

The 1,4-diazabicycloalkane derivative of the invention may be providedin any form suitable for the intended administration. Suitable formsinclude pharmaceutically (i.e. physiologically) acceptable salts, andpre- or prodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric acid, the formatederived from formic acid, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicacid, the benzenesulphonate derived from benzensulphonic acid, thebenzoate derived from benzoic acid, the cinnamate derived from cinnamicacid, the citrate derived from citric acid, the embonate derived fromembonic acid, the enantate derived from enanthic acid, the fumaratederived from fumaric acid, the glutamate derived from glutamic acid, theglycolate derived from glycolic acid, the lactate derived from lacticacid, the maleate derived from maleic acid, the malonate derived frommalonic acid, the mandelate derived from mandelic acid, themethanesulphonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a 1,4-diazabicycloalkane derivativeof the invention and its pharmaceutically acceptable acid addition salt.

Metal salts of a 1,4-diazabicycloalkane derivative of the inventioninclude alkali metal salts such as the sodium salt of a chemicalcompound of the invention containing a carboxy group.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, in particular themethyl-onium salt, the cycloalkyl-onium salts, and thecycloalkylalkyl-onium salts.

Steric Isomers

The 1,4-diazabicycloalkane derivative of the present invention may existin (+) and (−) forms as well as in racemic forms (±). The racemates ofthese isomers and the individual isomers themselves are within the scopeof the present invention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or I- (tartrates, mandelates,or camphorsulphonate) salts for example.

The 1,4-diazabicycloalkane derivative of the present invention may alsobe resolved by the formation of diastereomeric amides by reaction of thechemical compounds of the present invention with an optically activeactivated carboxylic acid such as that derived from (+) or (−)phenylalanine, (+) or (−) phenylglycine, (+) or (−) camphanic acid or bythe formation of diastereomeric carbamates by reaction of the chemicalcompound of the present invention with an optically active chloroformateor the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Methods of Preparation

The 1,4-diazabicycloalkane derivative of the invention may be preparedby conventional methods for chemical synthesis, e.g. those described inthe working examples. The starting materials for the processes describedin the present application are known or may readily be prepared byconventional methods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

The present invention relates to novel 1,4-diazabicycloalkanederivatives found to be cholinergic ligands at the nicotinicacetylcholine receptors (nAChR) and modulators of the monoaminereceptors, in particular the biogenic amine transporters 5-HT, DA andNE. Moreover, preferred compounds of the invention show selective α7activity.

In the context of this invention the term “modulator” covers agonists,partial agonists, antagonists and allosteric modulators of the receptor.

Due to their pharmacological profile the 1,4-diazabicycloalkanederivatives of the invention may be useful for the treatment of diseasesor conditions as diverse as CNS related diseases, PNS related diseases,diseases related to smooth muscle contraction, endocrine disorders,diseases related to neuro-degeneration, diseases related toinflammation, pain, and withdrawal symptoms caused by the termination ofabuse of chemical substances.

In a preferred embodiment the 1,4-diazabicycloalkane derivatives of theinvention are used for the treatment of diseases, disorders, orconditions relating to the central nervous system. Such diseases ordisorders includes anxiety, cognitive disorders, learning deficit,memory deficits and dysfunction, Alzheimer's disease, attention deficit,attention deficit hyperactivity disorder, Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles de laTourette's syndrome, depression, mania, manic depression, schizophrenia,obsessive compulsive disorders (OCD), panic disorders, eating disorderssuch as anorexia nervosa, bulimia and obesity, narcolepsy, nociception,AIDS-dementia, senile dementia, periferic neuropathy, autism, dyslexia,tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumaticsyndrome, social phobia, sleeping disorders, pseudodementia, Ganser'ssyndrome, pre-menstrual syndrome, late luteal phase syndrome, chronicfatigue syndrome, mutism, trichotillomania, and jet-lag.

In another preferred embodiment the 1,4-diazabicycloalkane derivativesof the invention may be useful for the treatment of diseases, disorders,or conditions associated with smooth muscle contractions, includingconvulsive disorders, angina pectoris, premature labour, convulsions,diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, prematureejaculation, and erectile difficulty.

In yet another preferred embodiment the 1,4-diazabicycloalkanederivatives of the invention may be useful for the treatment ofendocrine disorders, such as thyrotoxicosis, pheochromocytoma,hypertension and arrhythmias.

In still another preferred embodiment the 1,4-diazabicycloalkanederivatives of the invention may be useful for the treatment ofneurodegenerative disorders, including transient anoxia and inducedneuro-degeneration.

In even another preferred embodiment the 1,4-diazabicycloalkanederivatives of the invention may be useful for the treatment ofinflammatory diseases, disorders, or conditions, including inflammatoryskin disorders such as acne and rosacea, Chron's disease, inflammatorybowel disease, ulcerative colitis, and diarrhoea.

In still another preferred embodiment the 1,4-diazabicycloalkanederivatives of the invention may be useful for the treatment of mild,moderate or even severe pain of acute, chronic or recurrent character,as well as pain caused by migraine, postoperative pain, and phantom limbpain.

Finally the 1,4-diazabicycloalkane derivatives of the invention may beuseful for the treatment of withdrawal symptoms caused by termination ofuse of addictive substances. Such addictive substances includenicotine-containing products such as tobacco, opioids such as, heroin,cocaine and morphine, benzodiazepines and benzodiazepine-like drugs, andalcohol. Withdrawal from addictive substances is in general a traumaticexperience characterised by anxiety and frustration, anger, anxiety,difficulties in concentrating, restlessness, decreased heart rate andincreased appetite and weight gain.

In this context “treatment” covers treatment, prevention, prophylacticsand alleviation of withdrawal symptoms and abstinence as well astreatment resulting in a voluntary diminished intake of the addictivesubstance.

In another aspect, the 1,4-diazabicycloalkane derivatives of theinvention are used as diagnostic agents, e.g. for the identification andlocalisation of nicotinic receptors in various tissues.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of the1,4-diazabicycloalkane derivative of the invention.

While a 1,4-diazabicycloalkane derivative of the invention for use intherapy may be administered in the form of the raw chemical compound, itis preferred to introduce the active ingredient, optionally in the formof a physiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the 1,4-diazabicycloalkane derivative of theinvention, or a pharmaceutically acceptable salt or derivative thereof,together with one or more pharmaceutically acceptable carrierstherefore, and, optionally, other therapeutic and/or prophylacticingredients, know and used in the art. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not harmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route, which suits the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in drage, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition of the inventioncan be manufactured by any skilled person by use of standard methods andconventional techniques appropriate to the desired formulation. Whendesired, compositions adapted to give sustained release of the activeingredient may be employed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

The 1,4-diazabicycloalkane derivatives of the present invention arevaluable nicotinic and monoamine receptor modulators, and thereforeuseful for the treatment of a range of ailments involving cholinergicdysfunction as well as a range of disorders responsive to the action ofnAChR modulators.

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to modulation of cholinergic receptors and/ormonoamine receptors, and which method comprises administering to such aliving animal body, including a human, in need thereof an effectiveamount of a 1,4-diazabicycloalkane derivative of the invention.

In a preferred embodiment, the disease, disorder or condition relates tothe central nervous system.

In a preferred embodiment, the disease, disorder or condition isanxiety, cognitive disorders, learning deficit, memory deficits anddysfunction, Alzheimer's disease, attention deficit, attention deficithyperactivity disorder, Parkinson's disease, Huntington's disease,Amyotrophic Lateral Sclerosis, Gilles de la Tourette's syndrome,depression, mania, manic depression, schizophrenia, obsessive compulsivedisorders (OCD), panic disorders, eating disorders such as anorexianervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia,senile dementia, periferic neuropathy, autism, dyslexia, tardivedyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome,social phobia, sleeping disorders, pseudodementia, Ganser's syndrome,pre-menstrual syndrome, late luteal phase syndrome, chronic fatiguesyndrome, mutism, trichotillomania, and jet-lag.

In a another preferred embodiment, the disease, disorder or conditionare associated with smooth muscle contractions, including convulsivedisorders, angina pectoris, premature labour, convulsions, diarrhoea,asthma, epilepsy, tardive dyskinesia, hyperkinesia, prematureejaculation, and erectile difficulty.

In a third preferred embodiment, the disease, disorder or condition isrelated to the endocrine system, such as thyrotoxicosis,pheochromocytoma, hypertension and arrhythmias.

In a fourth preferred embodiment, the disease, disorder or condition isa neurodegenerative disorders, including transient anoxia and inducedneuro-degeneration.

In a fifth preferred embodiment, the disease, disorder or condition isan inflammatory disorder, including inflammatory skin disorders such asacne and rosacea, Chron's disease, inflammatory bowel disease,ulcerative colitis, and diarrhoea.

In a sixth preferred embodiment, the disease, disorder or condition ismild, moderate or even severe pain of acute, chronic or recurrentcharacter, as well as pain caused by migraine, postoperative pain, andphantom limb pain.

In a seventh preferred embodiment, the disease, disorder or condition isassociated with withdrawal symptoms caused by termination of use ofaddictive substances, including nicotine-containing products such astobacco, opioids such as heroin, cocaine and morphine, benzodiazepinesand benzodiazepine-like drugs, and alcohol.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10–500 milligrams daily, and especially 30–100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

A satisfactory result can, in certain instances, be obtained at a dosageas low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of thedosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred rangesare from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about10 mg/kg p.o.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

Example 1 Preparatory Example

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulfatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

1,4-Diazabicyclo[3.2.2]nonane (Intermediate compound) was preparedaccording to J. Med. Chem. 1993 36 2311–2320, and according to thefollowing slightly modified method.

To the solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g, 113 mmol)in absolute dioxane (130 ml) LiAlH₄ (4.9 g, 130 mmol) was added underargon. The mixture was refluxed for 6 hours and then allowed to reachroom temperature. Water (5 ml in 10 ml of dioxane) was added by drops tothe reaction mixture, the mixture was stirred for 0.5 hour and thenfiltered off via glass filter. The solvent was evaporated and theresidue was distilled using Kugelrohr apparatus at 90° C. (0.1 mbar) toyield 1,4-diazabicyclo[3.2.2]nonane (11.1 g, 78%) as colourlesshygroscopic material.

1,4-Diazabicyclo[3.2.2]nonan-3-one (Intermediate compound)

To the solution of 3-quinuclidinone hydrochloride (45 g, 278 mmol) in 90ml of water, hydroxylamine hydrochloride (21 g, 302 mmol) and sodiumacetate (CH₃COOHx3H₂O, 83 g, 610 mmol) were added, the mixture wasstirred at 70° C. for 1 hour and then cooled to 0° C. The separatedcrystalline material was filtered off (without washing!) and dried invacuo to yield 40.0 g of oxime.

The 3-quinuclidinone oxime (40.0 g) was added during 2 hours by smallportions to polyphosphoric acid* (190 g, prepared as described below*),preheated to 120° C. The temperature of the solution during the reactionwas kept at 130° C. After addition of all oxime the solution was stirredfor 20 minutes at the same temperature, then transferred to an enamelledvessel and allowed to reach room temperature. The acidic mixture wasneutralized by a solution of potassium carbonate (500 g in 300 ml ofwater), transferred into 2000 ml flask, diluted with 300 ml of water andextracted with chloroform (3×600 ml). The combined organic extracts weredried with sodium sulphate, the solvent evaporated and the solid residuedried up in vacuo to yield 30.0 g (77%) of the mixture of lactams.

Crystallization of the obtained mixture from 1,4-dioxane (220 ml) gave15.8 g (40.5%) of 1,4-diazabicyclo[3.2.2]nonan-3-one as colourless largecrystals with mp 211–212° C.

The filtrate was evaporated and the residue was chromatographed on asilica gel (Merck, 9385, 230–400 mesh) column with acetone as eluent.The solvent was evaporated and the residue recrystallized from ethyletanoate to yield 1,3-diazabicyclo[3.2.2]nonan-4-one (10.2 g, 26%) ascolourless fine crystals with mp 125–126° C.

Polyphosphoric Acid*

85% Orthophosphoric acid (500 g, 294 ml, 4.337 mol) was placed into 2000ml flask and then phosphor pentoxide (750 g, 5.284 mol) was added atroom temperature (ratio acid-pentoxide, 2:3). The mixture was stirred at200–220° C. for 2 hours to yield of 1250 g of polyphosphoric acid,containing 80% of P₂O₅.

2-Chloro-5-phenyl-1,3,4-thiadiazole (Intermediate compound)

2-Amino-5-phenyl-1,3,4-thiadiazole sulfate (25.12 g, 142 mmol) wasstirred in concentrated hydrochloric acid (300 ml) at 0° C. Sodiumnitrite (12.7 g, 184 mmol) was added during a period of 10 minutes. Thereaction mixture was stirred at 50° C. for 15 hours. The hydrochloricacid was evaporated. Aqueous sodium hydroxide (4 M, 250 ml) was addedand the the precipitate was filtered. Chromatography on silica gel withethyl acetate as solvent gave a pure product. Yield 15.5 g (56%).

Method A

4-(5-Phenyl-1,3,4-thiadiazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane fumaricacid salt (Compound A1);

A mixture of 1,4-diazabicyclo[3.2.2]nonane (1.28 g, 10.2 mmol),2-chloro-5-phenyl-1,3,4-thiadiazole (2.00 g, 10.2 mmol), triethylamine(2.83 ml, 20.3 mmol) and dioxane (20 ml) was stirred at reflux for 70hours. Aqueous sodium hydroxide (1 M, 25 ml) was added and the mixturewas extracted twice with ethyl acetate (2×20 ml). Chromatography onsilica gel with dichloromethane, 10% methanol and 1% aqueous ammonia assolvent gave the title compound as an oil. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Yield 0.95 g, 23%. Mp 150.9° C.

The following compounds are prepared in a similar manner:

-   4-[5-(2-Selenophenyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A2);-   4-[5-(3-Selenophenyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A3);-   4-[5-(2-Imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A4);-   4-[5-(4-Imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A5);-   4-[5-(5-Imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A6);-   4-[5-(1-Methyl-2-imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A7);-   4-[5-(1-Methyl-4-imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A8);-   4-[5-(1-Methyl-5-imidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A9);-   4-[5-(3-Pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A10);-   4-[5-(4-Pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A11);-   4-[5-(5-Pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A12);-   4-[5-(1-Methyl-3-pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A13);-   4-[5-(1-Methyl-4-pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A14);-   4-[5-(1-Methyl-5-pyrazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A15);-   4-[5-(2-Thiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A16);-   4-[5-(4-Thiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A17);-   4-[5-(5-Thiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A18);-   4-[5-(3-Isothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A19);-   4-[5-(4-Isothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A20);-   4-[5-(5-isothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A21);-   4-[5-(1,2,3-Oxadizol-4-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A22);-   4-[5-(1,2,3-Oxadizol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A23);-   4-[1,3,4-Oxadizol-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A24);-   4-[5-(3-Furazanyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A25);-   4-[5-(1,2,3-Triazol-4-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A26);-   4-[5-(1,2,3-Triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A27);-   4-[5-(1-Methyl-1,2,3-triazol-4-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A28);-   4-[5-(1-Methyl-1,2,3-triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A29);-   4-[5-(1,2,4-Triazol-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A30);-   4-[5-(1,2,4-Triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A31);-   4-[5-(1-Methyl-1,2,4-triazol-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A32);-   4-[5-(1-Methyl-1,2,4-triazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A33);-   4-[5-(1,3,4-Thiadiazol-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A34);-   4-[5-(1,2,4-Thiadiazol-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A35);-   4-[5-(1,2,4-Thiadiazol-5-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A36);-   4-[5-(3-Pyridazinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A37);-   4-[5-(4-Pyridazinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A38);-   4-[5-(1,3,5-Triazin-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A39);-   4-[5-(2-Quinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A40);-   4-[5-(3-Quinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A41);-   4-[5-(3-Isoquinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A42);-   4-[5-(3-Cinnolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A43);-   4-[5-(2-Indolizinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A44);-   4-[5-(2-Indolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A45);-   4-[5-(1-Methyl-2-indolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A46);-   4-[5-(2-Benzimidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A47);-   4-[5-(1-Methyl-2-benzimidazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A48);-   4-[5-(2-Benzothiazolyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A49);-   4-[5-(7-Phtalazinolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A50);-   4-[5-(2-Quinazolinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A51);-   4-[5-(2-Quinoxalinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A52);-   4-[5-(1,8-Naphthyridin-2-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A53);-   4-[5-(1,8-Naphthyridin-3-yl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A54);-   4-[5-(2-Acridinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A55); and-   4-[5-(3-Acridinyl)-1,3,4-thiadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound A56).    Method B

2-Mercaptobenzyl-5-phenyl-1,3,4-oxadiazole (Intermediate compound)

Benzylbromide (16.8 ml, 141 mmol) was added over a time period of 10minutes to a mixture of 5-phenyl-1,3,4-oxadiazole-2-thiol (commerciallyavailable) (25.2 g, 141 mmol), triethylamine (19.7 ml, 141 mmol) andethanol (250 ml) at room temperature.

The mixture was allowed to stir at room temperature for 3 hours. Aqueoussodium hydroxide (1 M, 250 ml) was added and the mixture was extractedtwice with dichloromethane (2×200 ml). Chromatography on silica gel withdichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave thetitle compound as an oil. Yield 34.2 g (90%).

Method C

5-(2-Furyl)-1,3,4-oxadiazole-2-thiol (Intermediate compound)

Carbon disuldide (16.5 g, 216 mmol) was added to a mixture of 2-furoichydrazide (13.6 g, 108 mmol), potassium hydroxide (6.68 g, 119 mmol) andmethanol (125 ml). The mixture was allowed to stir at room temperaturefor 30 minutes followed by reflux for 8 hours. The methanol wasevaporated. The aqueous phase was acidified to pH=4 with concentratedhydrochloric acid. The product was isolated by filtration. Yield 12.9 g(72%).

Method D

4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane fumaricacid salt (Compound D1)

A mixture of 2-mercaptobenzyl-5-phenyl-1,3,4-oxadiazole (Method B) (1.0g, 3.7 mmol), 1,4-diazabicyclo[3.2.2]nonane (0.47 g, 3.7 mmol) anddiisopropylethylamine (1.3 ml, 7.4 mmol) was stirred over for 4 days at100° C. Aqueous sodium hydroxide (1 M, 25 ml) was added and the mixturewas extracted twice with dichloromethane (2×20 ml). Chromatography onsilica gel with dichloromethane, 10% methanol and 1% aqueous ammonia assolvent gave the title compound as an oil. The corresponding salt wasobtained by addition of a diethyl ether and methanol mixture (9:1)saturated with fumaric acid. Yield 0.47 g, 33%. Mp 176.6–178.8° C.

The following compounds are prepared in a similar manner:

4-[5-(2-Furyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D2)

Was prepared according to Method D. Mp 175° C.

4-[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D3)

Was prepared according to Method D. Mp 190.1–191.2° C.

4-[5-(4-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D4)

Was prepared according to Method D. Mp 165.9–166.8° C.

4-[5-(2-Thienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D5)

Was prepared according to Method D. Mp 161.8–162.7° C.

4-[5-(3-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D6)

Was prepared according to Method D. Mp 176.8–177.5° C.

4-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D7)

Was prepared according to Method D. Mp 184.3–185.8° C.

4-[5-(3-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D8)

Was prepared according to Method D. Mp 126–164° C.

4-[5-(4-Phenyl-phenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D9)

Was prepared according to Method D. Mp 238–239° C.

4-[5-(2-Naphthyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonanefumaric acid salt (Compound D10)

Was prepared according to Method D. Mp 194.6–195.7° C.

In analogy herewith the following compounds are prepared:

-   4-[5-(3-Furyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D11);-   4-[5-(3-Thienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D12);-   4-[5-(2-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D13);-   4-[5-(2-Pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D14);-   4-[5-(3-Pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D15);-   4-[5-(1-Methyl-2-pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D16);-   4-[5-(1-Methyl-3-pyrrolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D17);-   4-[5-(2-Pyrimidinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D18);-   4-[5-(4-Pyrimidinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D19);-   4-[5-(5-Pyrimidinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D20);-   4-[5-(Pyrazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D21);-   4-[5-(2-Selenophenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D22);-   4-[5-(3-Selenophenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D23);-   4-[5-(2-Oxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D24);-   4-[5-(4-Oxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D25);-   4-[5-(5-Oxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D26);-   4-[5-(3-Isoxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D27);-   4-[5-(4-Isoxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D28);-   4-[5-(5-Isoxazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound 29);-   4-[5-(2-Imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D30);-   4-[5-(4-Imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D31);-   4-[5-(5-Imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D32);-   4-[5-(1-Methyl-2-imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D33);-   4-[5-(1-Methyl-4-imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D34);-   4-[5-(1-Methyl-5-imidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D35);-   4-[5-(3-Pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D36);-   4-[5-(4-Pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D37);-   4-[5-(5-Pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D38);-   4-[5-(1-Methyl-3-pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D39);-   4-[5-(1-Methyl-4-pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D40);-   4-[5-(1-Methyl-5-pyrazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D41);-   4-[5-(2-Thiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D42);-   4-[5-(4-Thiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D43);-   4-[5-(5-Thiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D44);-   4-[5-(3-Isothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D45);-   4-[5-(4-Isothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D46);-   4-[5-(5-Isothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D47);-   4-[5-(1,2,3-Oxadizol-4-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D48);-   4-[5-(1,2,3-Oxadizol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D49);-   4-[5-(1,3,4-Oxadizol-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D50);-   4-[5-(3-Furazanyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D51);-   4-[5-(1,2,3-Triazol-4-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D52);-   4-[5-(1,2,3-Triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D53);-   4-[5-(1-Methyl-1,2,3-triazol-4-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D54);-   4-[5-(1-Methyl-1,2,3-triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D55);-   4-[5-(1,2,4-Triazol-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D56);-   4-[5-(1,2,4-Triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D57);-   4-[5-(1-Methyl-1,2,4-triazol-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D58);-   4-[5-(1-Methyl-1,2,4-triazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D59);-   4-[5-(1,3,4-Thiadiazol-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D60);-   4-[5-(1,2,4-Thiadiazol-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D61);-   4-[5-(1,2,4-Thiadiazol-5-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D62);-   4-[5-(3-Pyridazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D63);-   4-[5-(4-Pyridazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D64);-   4-[5-(1,3,5-Triazin-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D65);-   4-[5-(2-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D66);-   4-[5-(3-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D67);-   4-[5-(5-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D68);-   4-[5-(6-Benzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D69);-   4-[5-(2-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D70);-   4-[5-(3-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D71);-   4-[5-(5-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D72);-   4-[5-(6-Benzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D73);-   4-[5-(2-Quinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D74);-   4-[5-(3-Quinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D75);-   4-[5-(3-Isoquinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D76);-   4-[5-(3-Cinnolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D77);-   4-[5-(2-Indolizinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D78);-   4-[5-(2-Indolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D79);-   4-[5-(1-Methyl-2-indolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D80);-   4-[5-(2-Benzimidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D81);-   4-[5-(1-Methyl-2-benzimidazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D82);-   4-[5-(2-Benzothiazolyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D83);-   4-[5-(7-Phtalazinolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D84);-   4-[5-(2-Quinazolinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D85);-   4-[5-(2-Quinoxalinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D86);-   4-[5-(1,8-Naphthyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D87);-   4-[5-(1,8-Naphthyridin-3-yl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D88);-   4-[5-(2-Acridinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D89);-   4-[5-(3-Acridinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D90);-   4-[5-(2-Dibenzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D91);-   4-[5-(3-Dibenzofuryl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D92);-   4-[5-(2-Dibenzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D93);-   4-[5-(3-Dibenzothienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D94);-   4-[5-(2-Phenoxazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D95); and-   4-[5-(3-Phenoxazinyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane    (Compound D96).

Example 2

In vitro Inhibition of ³H-α-Bungarotoxine Binding in Rat Brain

In this example the affinity of the compounds of the invention forbinding to α₇-subtype of nicotinic receptors is determined.

α-Bungarotoxine is a peptide isolated from the venom of the Elapidaesnake Bungarus multicinctus. It has high affinity for neuronal andneuromuscular nicotinic receptors, where it acts as a potent antagonist.

³H-α-Bungarotoxine labels nicotinic acetylcholine receptors formed bythe α₇ subunit isoform found in brain and the α₁ isoform in theneuromuscular junction.

Tissue Preparation

Preparations are performed at 0–4° C. Cerebral cortices from male Wistarrats (150–250 g) are homogenised for 10 seconds in 15 ml of 20 mM Hepesbuffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO₄ and 2.5 mM CaCl₂(pH 7.5) using an Ultra-Turrax homogeniser. The tissue suspension issubjected to centrifugation at 27,000×g for 10 minutes. The supernatantis discarded and the pellet is washed twice by centrifugation at27,000×g for 10 minutes in 20 ml of fresh buffer, and the final pelletis then re-suspended in fresh buffer containing 0.01% BSA (35 ml per gof original tissue) and used for binding assays.

Assay

Aliquots of 500 μl of homogenate are added to 25 μl of test solution and25 μl of ³H-α-bungarotoxine (2 nM, final concentration) and mixed andincubated for 2 hours at 37° C. Non-specific binding is determined using(−)-nicotine (1 mM, final concentration). After incubation, the samplesare added 5 ml of ice-cold Hepes buffer containing 0.05% PEI and poureddirectly onto Whatman GF/C glass fibre filters (pre-soaked in 0.1% PEIfor at least 6 hours) under suction, and immediately washed with 2×5 mlice-cold buffer.

The amount of radioactivity on the filters is determined by conventionalliquid scintillation counting. Specific binding is total binding minusnon-specific binding.

The test value is given as an IC₅₀ (the concentration of the testsubstance which inhibits the specific binding of ³H-α-bungarotoxin by50%).

The results of these experiments are presented in Table 1 below.

TABLE 1 Inhibition of ³H-α-Bungarotoxine Binding Compound No. IC₅₀ (μM)Compound 1A 0.0067 Compound D1 0.0058 Compound D5 0.022

1. A 1,4-diazabicycloalkane compound of Formula IV:

any of its enantiomers or any mixture of its enantiomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof, wherein Ar represents an aryl group selected from phenyl andnaphthyl, or a heteroaryl group selected from furanyl, thienyl andpyridinyl, which aromatic group may optionally be substituted one ormore times with substituents selected from the group consisting ofalkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy,alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl,cycloalkoxy-alkoxy, halogen, CF₃, CN, NO₂, NH₂, carboxy, carbamoyl,amido, sulfamoyl, phenyl and benzyl.
 2. The compound of claim 1, whereinAr may optionally be substituted one or more times with substituentsselected from the group consisting of alkyl, alkoxy, halogen, CF₃, CN,NO₂, NH₂ and phenyl.
 3. The compound of claim 1, wherein Ar representsphenyl, optionally substituted one or two times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, cycloalleoxy, halogen, CF₃, CN, NO₂, NH₂carboxy, carbamoyl, amido and sulfamoyl.
 4. The compound of claim 1,which is 4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;4-[5-(3-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;4-[5-(4-Merhoxyphenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;4-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;4-[5-(4-Phenyl-phenyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;4-[5-(2-Naphthyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;4-[5-(2-Furyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane;4-[5-(3-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonaue;4-[5-(4-Pyridyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane; or4-[5-(2-Tbienyl)-1,3,4-oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane; oran enantiomer or a mixture of enantiomers, or apharmaceutically-acceptable addition salt thereot or an N-oxide thereof.5. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1, any of its enantiomers or any mixtureof its enantiomers, or a pharmaceutically-acceptable addition saltthereof, together with at least one pharmaceutically-acceptable carrieror diluent.
 6. A method of the treatment or alleviation of a disease ora disorder or a condition of a living animal body, including a human,which disease or disorder is associated with withdrawal symptoms causedby termination of use of tobacco, heroin, cocaine, morphine,benzodiazepines, beuzodiazepine-like drugs, or alcohol, which methodcomprises the step of administering to such a living animal body,including a human, in need thereof a therapeutically effective amount ofa compound of claim 1, any of its enantiomers or any mixture of itsenantiomers, or a pharmaceutically-acceptable addition salt thereof. 7.The 1,4-diazabicycloalkane compound of clalm 1, wherein Ar representsphenyl, optionally substituted one or two times with substituentsselected from the group consisting of alkyl, cycloalkyl,cycloalkyl-alkyl, alkoxy, cycloalkoxy, halogen, CF₃, CN, NO₂, NH₂,carboxy, carbamoyl, amido, sulfamoyl, phenyl, and benzyl.
 8. The1,4-diazabicycloalkane compound of claim 7, wherein Ar representsphenyl, optionally substituted one or two times with substituentsselected fiom the group consisting of alkyl, alkoxy, halogen, CF₃, CN,NO₂, NH₂, and phenyl.